The experiments described in this proposal were designed to examine the pathophysiologic sequence of events which results in the generalized neuroinhibition of hepatic encephalopathy. Evidence is presented from preliminary studies that gamma-amino-butyric acid (GABA), the principal inhibitory neurotransmitter of the mammalian brain, and its neurotransmitter system may play an important role in hepatic coma in man. The proposed studies involve four broad areas: 1) Evaluating the source and metabolic economy of serum GABA in healthy and diseased humans; 2) Exploring new methods which may shed light on control of the blood-brain barrier; 3) Examining the anatomic distribution of GABA-ergic effects with 36Cl- autoradiography in animal models of hepatic coma and; 4) Measuring neurotransmitter receptor density and affinity in human autopsy specimens. All of these experiments make use of recently developed neurobiologic principles and methods to explore an old and tantalizing problem in clinical medicine. The goals of this research are several. The first would be to gain sufficient understanding of the pathophysiology of hepatic coma so that therapy might be rational rather than empiric. Second, increased understanding of blood-brain barrier permeability control in hepatic coma may lead to new therapeutic options. Third, insights into the pharmacodynamics of such widely used drugs as benzodiazepines and barbiturates would assist in rational therapy of patients with liver disease.